Wilfrid N. Raby

Atomoxetine Treatment for Cocaine Abuse and Adult Attention Deficit/Hyperactivity Disorder (ADHD): A Preliminary Open Trial

The purpose of this 12-week open-label trial was to evaluate the potential utility of atomoxetine for the treatment of attention deficit/hyperactivity disorder (ADHD) in cocaine-dependent treatment seekers. The sample consisted of 20 participants who met DSM-IV-TR criteria for ADHD and cocaine dependence. Using several measures to assess ADHD, there was a significant reduction in ADHD symptoms. There was no significant decrease in cocaine use throughout the trial. Taken together, although cocaine-dependent individuals showed some reduction in ADHD symptoms while receiving atomoxetine, the high dropout rate and lack of impact on cocaine use may limit its utility in adults with ADHD who are currently abusing cocaine.

A placebo-controlled trial of memantine for cocaine dependence with high-value voucher incentives during a pre-randomization lead-in period

Preclinical findings suggest that the inhibition of NMDA glutamatergic neurotransmission may have beneficial effects in the treatment of cocaine dependence. We hypothesized that memantine, a low potency, uncompetitive NMDA receptor antagonist, would be safe and effective in the treatment of cocaine dependence, particularly in preventing relapse to cocaine use in abstinent individuals. Cocaine dependent patients (N=112) were enrolled. The trial began with a 2-week placebo lead-in period during which patients received high-value voucher contingency management to induce abstinence. Participants were then randomized to receive either memantine 20mg bid (N=39) or placebo (N=42) for 12-weeks in combination with individual relapse-prevention therapy. The randomization was stratified by abstinence status during the lead-in period. The primary outcome was the weekly proportion of days of cocaine use. There were no significant differences in cocaine use outcome between the groups treated with memantine versus placebo. Thus, the efficacy of memantine 40 mg/d for the treatment of cocaine dependence was not supported. Urine-confirmed abstinence during the lead-in period was achieved by 44% of participants, and was a strong predictor of subsequent cocaine abstinence during the trial. This suggests that this clinical trial design, an intensive behavioral intervention during a lead-in period, resolves cocaine dependent patients into two subgroups, one that rapidly achieves sustained abstinence and may not need a medication, and another that displays persistent cocaine use and would most likely benefit from a medication to help induce abstinence. Targeting the latter subgroup may advance medication development efforts.

Concurrent Cannabis Use During Treatment for Comorbid ADHD and Cocaine Dependence: Effects on Outcome

Cannabis is the most widely used illicit substance in the United States with especially high prevalence of use among those with psychiatric disorders. Few studies have examined the relationship between concurrent cannabis use and treatment outcome among patients receiving treatment for comorbid substance abuse and psychiatric disorders. This study investigated the effects of cannabis use on treatment retention and abstinence from cocaine among cocaine dependent patients with Attention Deficit Hyperactivity Disorder (ADHD). Cocaine dependent patients diagnosed with current ADHD (DSM-IV, N = 92) aged 25 to 51 participated in a randomized clinical trial of methylphenidate for treatment of ADHD and cocaine dependence in an outpatient setting. The majority of patients (69%) used cannabis during treatment. Results suggest that moderate/intermittent cannabis users had greater retention rates compared to abstainers and consistent users (p = .02). This study is the first to examine concurrent cannabis use in cocaine dependent patients diagnosed with ADHD.

Intermittent Marijuana Use Is Associated with Improved Retention in Naltrexone Treatment for Opiate-Dependence

Naltrexone is a theoretically promising alternative to agonist substitution treatment for opioid dependence, but its effectiveness has been severely limited by poor adherence. This study examined, in an independent sample, a previously observed association between moderate cannabis use and improved retention in naltrexone treatment. Opioid dependent patients (N = 63), admitted for inpatient detoxification and induction onto oral naltrexone, and randomized into a six-month trial of intensive behavioral therapy (Behavioral Naltrexone Therapy) versus a control behavioral therapy (Compliance Enhancement), were classified into three levels of cannabis use during treatment based on biweekly urine toxicology: abstinent (0% cannabis positive urine samples); intermittent use (1% to 79% cannabis positive samples); and consistent use (80% or greater cannabis positive samples). Intermittent cannabis users showed superior retention in naltrexone treatment (median days retained = 133; mean = 112.8, SE = 17.5), compared to abstinent (median = 35; mean = 47.3, SE = 9.2) or consistent users (median = 35; mean = 68.3, SE = 14.1) (log rank = 12.2, df = 2, p = .002). The effect remained significant in a Cox model after adjustment for baseline level of heroin use and during treatment level of cocaine use. Intermittent cannabis use was also associated with greater adherence to naltrexone pill-taking. Treatment interacted with cannabis use level, such that intensive behavioral therapy appeared to moderate the adverse prognosis in the consistent cannabis use group. The association between moderate cannabis use and improved retention on naltrexone treatment was replicated. Experimental studies are needed to directly test the hypothesis that cannabinoid agonists exert a beneficial pharmacological effect on naltrexone maintenance and to understand the mechanism.

The effects of dronabinol during detoxification and the initiation of treatment with extended release naltrexone

BACKGROUND Evidence suggests that the cannabinoid system is involved in the maintenance of opioid dependence. We examined whether dronabinol, a cannabinoid receptor type 1 partial agonist, reduces opioid withdrawal and increases retention in treatment with extended release naltrexone (XR-naltrexone). METHODS Opioid dependent participants were randomized to receive dronabinol 30mg/d (n=40) or placebo (n=20), under double-blind conditions, while they underwent inpatient detoxification and naltrexone induction. Before discharge all participants received an injection of XR-naltrexone, with an additional dose given four weeks later. Dronabinol or placebo was given while inpatient and for 5 weeks afterwards. The primary outcomes were the severity of opioid withdrawal, measured with the Subjective Opioid Withdrawal Scale, and retention in treatment at the end of the inpatient phase and at the end of the 8-week trial. RESULTS The severity of opioid withdrawal during inpatient phase was lower in the dronabinol group relative to placebo group (p=0.006). Rates of successful induction onto XR-naltrexone (dronabinol 66%, placebo 55%) and completion of treatment (dronabinol 35%, placebo 35%) were not significantly different. Post hoc analysis showed that the 32% of participants who smoked marijuana regularly during the outpatient phase had significantly lower ratings of insomnia and anxiety and were more likely to complete the 8-week trial. CONCLUSION Dronabinol reduced the severity of opiate withdrawal during acute detoxification but had no effect on rates of XR-naltrexone treatment induction and retention. Participants who elected to smoke marijuana during the trial were more likely to complete treatment regardless of treatment group assignment.

A PLACEBO CONTROLLED TRIAL OF MEMANTINE AS AN ADJUNCT TO ORAL NALTREXONE FOR OPIOID DEPENDENCE

BACKGROUND Preclinical findings suggest that the inhibition of NMDA glutamatergic neurotransmission may have beneficial effects in the treatment of opioid dependence. AIMS We hypothesized that memantine, a low-potency, uncompetitive NMDA receptor antagonist, would be safe and effective when used as an adjunct to oral naltrexone in the treatment of opioid dependence, particularly in preventing relapse to opiate use in detoxified individuals. METHODS Opioid-dependent participants (N=112) were enrolled. Following detoxification all participants were inducted onto oral naltrexone and were randomized to receive memantine 15 mg bid (N=27), memantine 30 mg bid (N=27) or placebo (N=27) for 12-weeks in combination with naltrexone 50mg/day and individual relapse-prevention therapy. The primary outcome was the retention in treatment since treatment dropout is most commonly associated with relapse to opiate use. RESULTS Twenty-six percent of participants withdrew from treatment prior to starting naltrexone. Of those that were randomized 35% completed 4 weeks only, and 24% completed all 12 weeks of treatment. There was no significant difference in treatment retention or heroin use, opiate withdrawal symptoms and craving between the groups treated with memantine vs. placebo. CONCLUSION Thus, the efficacy of memantine 30 or 60 mg/day as an adjunct to oral naltrexone for the treatment of opiate dependence was not supported.

Antisocial Behavioral Syndromes in Cocaine and Cannabis Dependence

Antisocial personality disorder (ASPD) is highly associated with substance use disorders (SUD). In addition to the full ASPD syndrome, which requires both childhood conduct disorder and the adult features, other antisocial behavioral syndromes, including conduct disorder (CD) alone without the adult syndrome, and the adult antisocial behavioral syndrome without childhood CD (AABS) are also frequently diagnosed in patients with SUD. The aim of this study was to compare the rates of these various ASPD syndromes between cocaine- and cannabis-dependent individuals seeking treatment. A structured interview for ASPD excluding symptoms that occurred solely in the context of substance use was conducted in 241 outpatients (cocaine dependence, n = 111; cannabis dependence, n = 130). Overall, the proportion of substance-dependent individuals in this study with AABS was significantly larger than the proportion with ASPD (30.9% vs. 17.3%). A diagnosis of CD-only, where CD did not progress to ASPD, was uncommon. No significant differences in the prevalence of antisocial behavioral syndrome diagnoses were found between cocaine- and cannabis-dependent patients. Antisocial behavioral syndrome diagnosis did not influence treatment retention. Antisocial behavioral syndromes are commonly diagnosed in patients with SUD and future research should evaluate prognostic implications of AABS compared to ASPD in a variety of clinical treatment settings.

Severity of dependence and motivation for treatment: comparison of marijuana- and cocaine-dependent treatment seekers.

Abstract Although marijuana dependence is prevalent, most individuals with marijuana dependence do not seek treatment. There are few data characterizing treatment seeking marijuana-dependent patients compared to patients presenting for treatment of other drugs regarding the severity of illness and motivation for treatment. Forty-two marijuana-dependent individuals were compared to 58 cocaine-dependent individuals seeking treatment. Compared to cocaine-dependent patients, those with marijuana dependence were younger and less likely to be dependent on alcohol or other drugs. Both groups had similar rates of comorbid anxiety and affective disorders. Marijuana-dependent individuals had lower total number of dependence symptoms but had a higher percentage of individuals endorsing withdrawal symptoms. Although marijuana-dependent individuals had less outpatient treatment exposure, the difference between the two groups was not significant and motivation for change, based on the University of Rhode Island Change Assessment, was similar for both groups of treatment seekers. However, the Circumstances, Motivation, Readiness for Treatment Scale suggested that cocaine-dependent individuals were more motivated for treatment. Taken together, these data suggest that treatment seeking marijuana-dependent individuals have substantial withdrawal dependence symptomatology although it is less clear if they are as motivated to seek out treatment as cocaine-dependent treatment seekers.

Betting on Change: Modeling Transitional Probabilities to Guide Therapy Development for Opioid Dependence

This study investigated the process of change by modeling transitions among four clinical states encountered in 64 detoxified opiate-dependent individuals treated with daily oral naltrexone: no opiate use, blocked opiate use (i.e., opiate use while adhering to oral naltrexone), unblocked opiate use (i.e., opiate use after having discontinued oral naltrexone), and treatment dropout. The effects of baseline characteristics and two psychosocial interventions of differing intensity, behavioral naltrexone therapy (BNT) and compliance enhancement (CE), on these transitions were studied. Participants using greater quantities of opiates were more likely than other participants to be retained in BNT relative to CE. Markov modeling indicated a transition from abstinence to treatment dropout was approximately 3.56 times greater among participants in CE relative to participants in BNT, indicating the more comprehensive psychosocial intervention kept participants engaged in treatment longer. Transitions to stopping treatment were more likely to occur after unblocked opiate use in both treatments. Continued opiate use while being blocked accounted for a relatively low proportion of transitions to abstinence and may have more deleterious effects later in a treatment episode. (PsycINFO Database Record (c) 2009 APA, all rights reserved).

Early Abstinence in Cocaine Dependence: Influence of Comorbid Major Depression

Cocaine dependence (CD) is often accompanied by major depressive disorder (MDD). The comorbid condition (CD + MDD) is especially difficult to treat, with relapse possibly made more likely by intensified dysphoria during abstinence in the setting of MDD. We studied treatment-seeking CD + MDD volunteers, currently depressed, and a comparison CD group over three days of inpatient monitored abstinence. At admission, Beck Depression Inventory (BDI) and anxiety scores differed significantly between groups. By Day 3, BDI scores improved for both CD and CD + MDD groups. The mood response to cocaine cessation among CD + MDD individuals resembled that of CD participants, contrary to some expectations.